ABSTRACT: Despite therapeutic advances, heart failure remains a major cause of morbidity and mortality. One approach to improve outcomes for patients with heart failure is to replace lost or dysfunctional tissue through therapeutic heart regeneration. While the concept of therapeutic heart regeneration was once relegated to science fiction, recent advances in stem cell and developmental biology have allowed for regeneration to become a possibility. Work in model systems with robust regenerative capacity, such as zebrafish and neonatal mice, has revealed a vigorous angiogenic response to injury that is not present in the adult mammalian heart. Through our work in zebrafish, we have found that overexpressing vegfaa is sufficient to induce angiogenesis and an ectopic regenerative program. Accordingly, here we propose a set of studies to evaluate whether VEGFA can also stimulate and enhance regenerative responses in the mammalian heart. Additionally, we propose work to identify novel genetic regulators of angiogenesis to expand the set of angiogenic factors that may be able to stimulate tissue regeneration. The studies outlined here can conceptually link revascularization approaches to regenerative biology and result in new targets to manipulate cardiac growth responses. Thus, this work has high potential for informing novel methods for therapeutic human heart regeneration.